Certain
chemotherapeutics (e.g., oxaliplatin, OXA) can evoke effective
antitumor immunity responses by inducing immunogenic cell death (ICD).
Unfortunately, tumors always develop multiple immunosuppressive mechanisms,
such as the upregulation of immunosuppressive factors, to counteract
the effects of immunogenic chemotherapy. Indoleamine 2,3-dioxygenase-1
(IDO1), a tryptophan catabolic enzyme overexpressed in tumor-draining
lymph nodes (TDLNs) and tumor tissues, plays a pivotal role in the
generation of the immunosuppressive microenvironment. Reversing IDO1-mediated
immunosuppression may strengthen the ICD-induced immune response.
Herein, we developed a nanoenabled approach for IDO1 pathway interference,
which is accomplished by delivering IDO1 siRNA to both TDLNs and tumor
tissues with the help of cationic lipid-assisted nanoparticles (CLANs).
We demonstrated that the contemporaneous administration of OXA and
CLANsiIDO1
could achieve synergetic antitumor
effects via promoting dendritic cell maturation, increasing tumor-infiltrating
T lymphocytes and decreasing the number of regulatory T cells in a
subcutaneous colorectal tumor model. We further proved that this therapeutic
strategy is applicable for the treatment of orthotopic pancreatic
tumors and offers a strong immunological memory effect, which can
provide protection against tumor rechallenge.
Activation of the phagocytosis of macrophages to tumor cells is an attractive strategy for cancer immunotherapy, but the effectiveness is limited by the fact that many tumor cells express an increased level of anti‐phagocytic signals (e.g., CD47 molecules) on their surface. To promote phagocytosis of macrophages, a pro‐phagocytic nanoparticle (SNPACALR&aCD47) that concurrently carries CD47 antibody (aCD47) and a pro‐phagocytic molecule calreticulin (CALR) is constructed to simultaneously modulate the phagocytic signals of macrophages. SNPACALR&aCD47 can achieve targeted delivery to tumor cells by specifically binding to the cell‐surface CD47 and block the CD47‐SIRPα pathway to inhibit the “don't eat me” signal. Tumor cell‐targeted delivery increases the exposure of recombinant CALR on the cell surface and stimulates an “eat me” signal. Simultaneous modulation of the two signals enhances the phagocytosis of 4T1 tumor cells by macrophages, which leads to significantly improved anti‐tumor efficacy in vivo. The findings demonstrate that the concurrent blockade of anti‐phagocytic signals and activation of pro‐phagocytic signals can be effective in macrophage‐mediated cancer immunotherapy.
A novel type of multi-stimuli responsive dendrimer with thermo-, pH-, and CO2-responsiveness was developed through facile modification of polyamidoamine dendrimers with various N-dialkylaminoethyl carbamate moieties.
APP nanoparticle was developed to deliver DOX for the treatment of PCNSL. The results indicated that APP@DOX could overcome the BBB, and significantly prolong the survival time of mice with an intracranial SU-DHL-2 lymphoma xenograft.
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